5-nitro-2-substituted thiophenes and process



Patented June 1, 1954 UNITED STATES PATENT- OFFICE?5-NITRO-2-SUBSTITUTEIY THIOPHENES' AND PROCESS Edyvard C. Hermann,WilmingtoifiDeL, assignq'r to -E-.--I'. du--Pont -de Nemours andCompany; Wilmington,- Deli-, as corporatio'nof Delaware NdnmwinaApplicationMay 18, 1951, Serial No. 227,11

8 Claims: 01. 260-33212 This invention relates -tocertain- 5 -nitro-2substituted thiophene's1""-Moreparticularly; it

relates to the three "compounds 5-nitro-2*-thi phenecarboxaldehydei5-1Ti1310-z t i p n ahff anediol "diacetate, and 5-nitro-2-thi0pheh m tanediol 'di-n-propionate; and to processes-for making the compounds.

The 5-nitro-2-sub'stituted""thiophene [com-1 pounds of "the "inventionare representedby theformula Z-thiophenemetha'nediol di (aliphaticcarboxal- I ate)" in which the aliphatic carboxaiate radical" isacetate'or n-propionate depending 'upon the acid anhydride reactantused. The'reactionds in-f itiated by and'carried out in the presence ofa catalytic amountof a mineral acid and'the prod:

uct of the reaction is then nitrated in the pres? ence 'of one'of theaforementioned acid anhydrides to give the desired'5-nitro-z thiophene'fi-nitro'g' u 2-thiophenecarboxaldehyde is easily 'obtained byhydrolyzing either of the 5-nitro-z thiophene' methanediol di(aliphaticoarboxa1ate) methanediol di aliphatic carb-oxalate)s.

In carrying out the processes of the invention; the reaction of2-thiophenecarboxaldehyde"with th acid anhydride is initiated by theaddition of a mineral acid. The reaction cannot-be in duced' in theabsence of such acid. Once in-- itiated by the mineral'acid catalyst,-the reaction is exothermic and'pro'ceeds rapidly;

Sulphuric acid is the preferred mineral acid catalyst used to catalyzethe 2 thiophenecarboxaldehyde-acid anhydride reaction tho othefminera'lacids such as hydrochloric,' nitric, phosphoric," and hydrofluoric,for example; can 'be The amountof mineral acidrequired' to catalyze the2-thi'oplienecarboxaldehyde-acid anhyd'ride reaction varies with theparticular min eralacid employed and with' the purity of the" reactantsbut, in general; a very small amount is required 'in propolti'dfito thequaiit'ityhf 'rea'OR tants;' thusfusing sulphuric acid; for example, thereaction of acetic anhydi'i'de or n-prdpioriid anhydride' with pure2-thiophenecarbox'al'de hyde' is readilyinitiat'ed by using'as littleasone partby weight of concentrated sulphuricaci'd'for each 1500 to2,000"parts'by Weight of the"a1de'-' hyde. 1 Larger amounts ofthe'mineral acid" can" be used but there is'n'o'ad'varitag'e iiihavingniore than is needed to startthereaction and this minimum amountis readily determined, in each case simply byadding a mineral acid to amixture of the" reactants until the" exothermic reaction -starts.

It is much preferre'd t'o haVethQQ-thiophene carbox aldehyde 1 employedin the" -'-p1'ocesses---of the invention substantially free ofcontaminants which ten'dto hinder thereationwith the acid anhydride.Some commercial 2-thiophenecarbox'a-ldehyde, for example reacts"slowlyor -i-ncompletely with acetic or propionie' a'hhydrid'es if atall;-notwlthstaiidirlg th additioIl 0f -rel-' ativelylarge amounts ofmineral acidcata-IySt: Commercial --2 -thiophenecarboxaldehyde -'f re"-quently' has a dark color and -anacrid odor: Such product can be freedof the color and the acridodor by w'ashir'1-g--"first withaqueousalkaline solution, their with an-"aqueous acid solution} followed bydistillation of the aldehyde} i-There suiting purifiedproduct iswatenwhitefihasapleasant benzaldehydedi ke odor ar rea'ct'sreadily withacetic -'o'r propioriic anhydri'de in the presence of a minor amount of'a mineral acids The next-step inthe proces'ses-of' the invention, thehitration -of Z- thiopIienemtIiaIiBd i OT di cart phatic'carboxala-te)is carried (meander re ati ly mild-'nit'ratin'gconditions -'-Thusthe-magnets can-be suitablycarriedout fig-bringing together the 'di(aliphatic-- carboii ala with" "an acyl nitrate suc'h' as acetjrlnitrate or n-propiony-l ni-- trate' w'ith agi-tatien at arela ylyiow-temperature,- say, a'round 0 C. or less'i'- Preferably-the nitratiohis carried out by sitspending the fi-jhiijililfihifihhdi dittliph'aticcarboxalate) iri a -bedy or acid a hhydr such as acetic anhydride orn-propionic anl'iy'- dride ahd then 'addin fuming" and acid saw-1y thereaCtin'QinassS The acid' 'anhydr e is used in' at leastthe'stoichi'oiiietri'c amountirquirdto rea'ct"with" the filming nitricacid to form-stag corresponding 'acyfhitrate.

The 5 mire: 2 thioplienerfiethanediol' dia'e tate or di-n-propionateprepared as above are readily converted to the5-nitro-2-thiophenecarboxaldehyde of the invention by acid hydrolysiscarried out according to conventional hydrolysis techniques. Thus thehydrolysis to 5-nitro-2- thiophenecarboxaldehyde is efiected by heatingan acidified aqueous suspension of the 5-nitro-2- thiophenemethanedioldi(aliphatic carboxalate). The acidifying agent is a mineral acid,prefer ably sulfuric or hydrochloric acid. Since the nitrateddi(aliphatic carboxalates) used in this step are relatively insoluble inwater, the hydrolysis rate can be increased by bringing the reactantsinto solution by addition of a suitable solvent such as ethanol to theaqueous mass.

The compounds of the invention have useful fungicidal and bactericidalproperties and have considerable activity against the oocysts ofEimerz'a tenella. They are particularly valuable EXAMPLE I5-nitro-2-thiophenemethanediol diacetate 105 parts by weight of2-thiophenecarboxaldehyde and 102 parts by weight of acetic anhydridewere mixed at room temperature in a vessel equipped with a refluxcondenser. Approximately 0.1 part by weight of concentrated sulfuricacid was added to the mixture. Immediately, an exothermic reactionstarted.

After the exothermic reaction had subsided, the reaction mass was cooledand the entire mass crystallized. The crystalline product was broken up,washed on a filter with parts by weight of ether, then washed withwater, then finally dried overnight in a vacuum over phosphorouspentoxide.

190 parts by weight (99% yield) of the crude 2-thiophenemethanedioldiacetate was obtained. On recrystallization of this material from etherand decolorization with charcoal there was obtained 168 parts by weight(88% yield) of colorless crystals, M. P. 6768 C.

Analysis.Calcd. for C9H1004S: C, 50.45; H, 4.70; S, 14.96. Found: C,50.48; H, 4.90; S, 15.21.

80 parts by weight of 2-thiophenemethanediol diacetate prepared as abovewas stirred into 63.6 parts by weight of acetic anhydride to form asuspension of the diacetate. The mixture was cooled to 5 C. and withcontinuous stirring, 39.2 parts by weight of fuming nitric acid (D=1.5)was added slowly over a period of 86 minutes while maintaining thetemperature of the reacting mass between about 5 and 10 C. Stirring andcooling were continued for one hour after completion of nitric acidaddition. The reaction mass was then in the form of a yellow paste.

100 parts by weight of water were added to the yellow paste and themixture was at once poured into 250 parts by weight of ice water. Theinsoluble product was separated by filtration and washed with wateruntil the filtrate was nearly colorless. The moist filter cake wasrecrystallized at once from absolute alcohol, including treatment withdecolorizing charcoal, and washed with pctroleum naphtha. Yield, 71parts by weight (73%) of 5-nitro-2-thiophenemethanediol diacetate, aslightly yellow colored crystalline powder, M. P. 64-69" C. A sample ofthe product recrystallized five times from ether had a constant meltingpoint of 72-73 C.

AnaZysis.-Calcd. for CQHQNOSSZ C, 41.71; H, 3.50; N, 5.40; 5, 12.37.Found: C, 42.23; H, 3.56; N. 5.26; S, 12.36.

EXAMPLE II S-nitro-Z-thiophenecarboscaZdehyde A mixture of 51.8 parts byweight of 5-nitro-2- thiophenemethanediol diacetate (M. P. fi l-69 C.)prepared as above, 100 parts by weight of water, parts by weight ofethanol and about 19 parts by weight of concentrated sulfuric acid washeated under reflux for thirty minutes. The hot solution was thenfiltered and the filtrate chilled to induce crystallization.

lhe product 5-nitro-2-thiophenecarboxaldehyde crystallized from thereaction mass in the form of pale yellow needles. The crystallineproduct was washed with cold water and dried in a vacuum over calciumchloride. A yield of 27.3 parts by weight (87%) of5-nitro-2-thiophenecarboxaldehyde was obtained, M. P. 68-70" C. Onrecrystallization from approximately parts by weight of 50% aqueousethanol, 21.7 parts by weight (69%) of the product was obtained, M. P.73-74 C.

For analysis a sample of the 5-nitro-2-thiophenecarboxaldehyde of thisexample was recrystallized from 50 ethanol to a constant M. P. of 735-74 C. and dried in a vacuum desiccator over phosphorous pentoxide at roomtemperature.

Analysis.Calcd. for CsHsNOsSI C, 38.21; H, 1.92; N, 8.92; S, 20.40.Found: C, 38.15; H, 2.25;

EXAMPLE III 5-mtro-2-thiophenecarbomaldehyde was then cooled to 5 C. bythe direct addition.

of Dry Ice. During the cooling operation, pale green crystals began toappear when the temperature reached 21 C.

181 parts by weight of fuming nitric acid (D=1.5) was added dropwise tothe resulting suspension of the pale green crystals over a period of 63minutes while adding Dry Ice to maintain the temperature of the reactionmixture at -5 C. The resulting red nitration mixture was then quenchedwith a mixture of ice and water. After filtering and washing at 0, 549parts by weight of a brilliant yellow crystalline product,5-nitro-2-thiophenemethanediol diacetate, was obtained (damp weight).

The crude 5-nitro-2thiophenemethanediol diacetate was hydrolyzed,without further drying or purification, by refluxing for 30 minutes with124 parts by weight of concentrated sulfuric acid in 1400 parts byweight of approximately 50% aqueous ethanol. The hydrolysate was cooledby the direct addition of ice, and 365 parts by weight of crude5-nitro-2-thiophenecarboxaldehyde was astern obtained-as a dark brownprecipitatef'F This maii'eateupimerrenux torso-minutes? rnenccseiuterialwaszrredissolvedrinu50%=ethanol, treated withdecolorizing charcoal, andcooled to, crystal- --1ize a brown, needle-like product (164 part's bydiy weight, melting point 63 70 C.) A second EXAMPLE IV5-m'tro-2-thiophenemethanediol dipropionate 105 parts by weight of2-thiophenecarboxaldehyde and 130 parts by weight of propionic anhydridewere mixed at room temperature in a vessel equipped with a refluxcondenser. Approximately 0.1 part by weight of concentrated sulfuricacid was added to the mixture. Immediately an exothermic reactionstarted. After the exothermic reaction had subsided, the reactionmixture was allowed to cool to room temperature and was then poured into2500 parts by weight of ice water. The green-colored oil which separatedfrom the resulting mixture was recovered by extracting the mixture twotimes with ether. The combined ether extracts were dried and the etherwas then removed by distillation under reduced pressure. leaving agreen, oily residue. This residue was distilled under vacuum through a 4Vigreux type column. 130 parts by weight of 2-thiophenemethanedioldipropionate was recovered as a fraction with B. P. 9394 C. (0.1 mm.Hg), n

AnaZysis.-Ca1cd. for C11H14O4S: C, 54.53; H, 5.82; S, 13.23. Found: C,55.11; H, 6.09; S, 13.91.

111 parts by weight of the 2-thiophenemethanediol dipropionate preparedas above was stirred into approximately 100 parts by weight of aceticanhydride. The mixture was cooled to 5 C. and with continuous stirring,34 parts by weight of yellow fumin nitric acid (D=1.5) was added slowlyover a period of approximately 80 minutes while maintaining thetemperature of the reacting mass between 5 and -10 C. Stirring andcoolin were continued for 23 minutes after completion of the nitric acidaddition.

The reaction mixture so obtained was poured into 1000 parts by weight ofice water. The resulting mixturewas allowed to stand at for one hour andthen the insoluble yellow oil phase was recovered by extracting'themixture twice with ether. The combined ether extracts were washed twicewith saturated sodium bicarbonate solution and then dried. The ether wasremoved by distillation under reduced pressure and the residue wasdistilled under vacuum through a 6 Vigreux column. Crude-nitro-2-thiophenemethanediol dipropionate was obtained as 4'7 parts byweight of a yellow oil with B. P. 145-155 C. (0.5 to 0.75 mm. Hg).

EXAMPLE V.

5 mitro-Z-thiophenecarboxaldehyde A mixture of 58 parts by weight of5-nitro-2- tion was filtered and cooled and then pourec l into e-resulting mixture was extra-ctew wice -wi-th etherf lt-Bhe ether wasremovedfrom the dried combined ex- ---"tr'actsby distillationunder-reduced pressurey g-ivparts by weight of ethanol, and about 19parts by weight of concentrated sulfuric acid was ing a residueconsistingofi yellow"crystalline material plus -oilfi l The crystallinemater-ial wasisem ar a-ted by ii ltr'ation and washed wi-th petroleumethe'r (BL Ps -60 7 1 C.)'I- 'i I- he crystallinernaterial was purifiedby sublimation at 62 c. ::.a}nd208amn. Hg pressure, giving a total of 13parts by weight of 5-nitro-2-thiophenecarboxaldehye as yellow needles,M. P. 71.5-7350.

EXAMPLE v1 S-m'tro-Z-thiobhenemethrmediol dipropionate Approximately 1part by weight of concentrated sulfuric acid was added to a mixture ofparts by weight of crude 5-nitro-2-thiophenecarboxaldehyde (M. P. 66-71C.), 86.9 parts by weight of propionic anhydride and 100 parts by weightof dioxane. Immediately there was an exothermic reaction. The resultingmixture was stirred for one hour and then poured into 2500 parts byweight of ice water. The resulting mixture was extracted with ether andthe ether extract was dried. The ether was then removed from the driedextract by distillation under reduced pressure. The residue wasdistilled under reduced pressure through a 4" Vigreux type column. Crude5-nitro-2-thiophenemethanediol dipropionate was obtained as parts byweight of I yellow oil with B. P. -158 (0.85-08. mm. Hg).

Upon redistillation, 95 parts by weight of a yellow oil was obtained, B.P. 145-153.5 C. (035-03 mm. Hg).

I claim:

1. The method comprising forming 2-thiophenemethanediol di(aliphaticcarboxalate), wherein the aliphatic carboxalate radical is selected fromthe group consisting of acetate and n-propionate, by reactingZ-thiophenecarboxaldehyde, in the presence of a catalytic amount of amineral acid, with an acid anhydride selected from the group consistingof acetic anhydride and n-propionic anhydride, and nitrating said di-(aliphatic carbcxalate) compound in the presence of one of said acidanhydrides.

2. In the method for the preparation of 5- nitro 2 thiophenemethanedioldiacetate, the steps comprising forming 2-thiophenemethanediol diacetateby reacting 2-thiophenecarboxa1- dehyde, in the presence of a catalyticamount of a mineral acid, with acetic anhydride, and nitrating saiddiacetate in the presence of acetic.

anhydride.

3. In the method for the preparation of 5-nitro-2-thiophenecarboxaldehyde, the steps comprising forming2-thiophenemethanediol diacetate by reacting 2-thiophenecarboxaldehyde,in the presence of a catalytic amount 'of a mineral acid, with aceticanhydride, nitrating said diacetate in the presence of acetic anhydride,and hydrolyzing the nitrated diacetate.

4. In a method for the preparation of 5-nitro-2-thiophenecarboxaldehyde, the steps comprising forming2-thiophenemethanediol diacetate by reacting 2-thiophenecarboxaldehyde,in the presence of a catalytic amount of sulfuric acid, with aceticanhydride, nitrating said diacetate by slowly adding fuming nitric acidto a mixture of the diacetate with acetic anhydride, and hydrolyzing theresulting nitrated diacetate by heating it in the presence of aqueoussulfuric acid References Cited in the file 01 this patent solution. NITD TEN 5. A 5-nitro-substituted thiophene compound U E STATES PA Tsselected from the class consisting of 5-nitro-2- Number Name Datethiophenecarboxaldehyde, 5 nitro-2-thiophene- 5 2,502,114 Wltte et a11950 methanediol diacetate and 5-nitro-2-thi0phene- OTHER REFERENCESmethanediol di-n-propionate. n T 1 6. 5-nitro-2-thiophenecarboxa1dehyde.$315 Pharm' and v0 7. 5-nitro-2-thiophenemethanedio1 diacetate. 8. 5nitro 2 thiophenemethanediol di n 10 propionate.

5. A 5-NITRO-2-SUBSTITUTED THIOPHENE COMPOUND SELECTED FROM THE CLASSCONSISTING OF 5-NOTRO-2THIOPHENECARBOXALDEHYDE, 5-NOTRO-2-THIOPHENEMETHANEDIOL DIACETATE AND5-NITRO-2-THIOPHENEMETHANEDIOL DI-N-PROPIONATE.